TWI259080B

TWI259080B - Fluoro substituted cycloalkanoindoles, compositions containing such compounds and methods of treatment

Info

Publication number: TWI259080B
Application number: TW092101476A
Authority: TW
Inventors: Carl Berthelette; Nicolas Lachance; Lianhai Li; Claudio Sturino; Zhaoyin Wang
Original assignee: Merck Frosst Canada Ltd
Priority date: 2002-01-24
Filing date: 2003-01-23
Publication date: 2006-08-01
Also published as: KR20040075109A; CY2009004I2; PL370427A1; IL188844A0; JP2005518413A; IS8887A; FR09C0010I1; CA2471952C; PL208527B1; NO2009013I1; ES2391747T3; IS2633B; DOP2003000566A; KR100859230B1; NL300377I2; NZ533786A; CY2009004I1; US20060069148A1; US20030158246A1; CN101851191A

Abstract

Fluoro substituted cycloalkanoindole derivatives are antagonists of prostaglandins, and as such are useful for the treatment of prostaglandin mediated diseases.

Description

1259080 發明說明續頁 (5) 之為互變體。該實例可為酮-烯醇互變體之酮及其烯醇形式。單獨之互變體及其混合物均包含於式I之化合物中。式I之化合物可藉由例如自適用之溶劑如甲醇或乙酸乙酯或其混合物部分結晶，分離成對映體之非立體異構物對。因此獲得之對映體對可藉由慣用之方式分離成單獨之立體異構物，例如藉由適用光學活化之酸或鹼作為溶解劑，或藉由對掌性分離技術如以使用對掌性管柱之HPLC分離。另外，一般式I或la化合物之對映體可藉由使用光學上純之起始物質或已知結構之試劑，立體特定的合成製備。 “醫藥接受性鹽”係指由醫藥接受性無毒鹼（包含無機鹼及有機鹼 >製備之鹽。由無機鹼衍生之鹽包含鋁、銨、鈣、銅、鐵、經、鎂、巍鹽、鐘、钾、鈉、鋅等。最佳者為铵、鈣、鎂、鉀及鈉鹽。由醫藥接受性有機無毒鹼衍生之鹽包含一級、二級及三級胺，經取代之胺包含天然發生之經取代胺、環狀胺，及驗性離子交換樹脂，如精胺酸、甜菜驗、咖啡因、膽鹼、N，N’-二芊基乙二胺、二乙胺、2-二乙基胺基乙醇、2-二甲基胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、 N-乙基峰啶、葡胺、葡糖胺、組胺酸、海拉明（hydrabamine)、異丙胺、'絲胺酸、甲基葡胺、嗎啉、哌畊、哌啶、聚胺樹脂、普卡因、嘌呤、可可鹼、三乙胺、三甲基胺、三丙基胺、胺基丁三醇等。當本發明化合物為鹼時，可由包含無機酸及有機酸之醫 1259080 發明說明續頁 ⑻ 可與載劑物質併用產生單一劑量形式之活性成份量會隨著主要之治療及投藥之特殊方式而變。例如，人類口服投藥用之調配物可含0.05毫克至5克之與適用及方便量之載劑物質（其可在總組合物之約5至約99.95%間變化）化合之活性劑。投藥單位形式通常含約0.1毫克至約0.4克活性成份，通常為0.5毫克、i毫克、2毫克、5毫克、10毫克、25毫克、50 毫克、100毫克、200毫克或400毫克。醫藥組合物本發明另一目的係提供一種醫藥組合物，該組合物包括式I之化合物及醫藥接受性載劑。至於醫藥組合物中之“組合物”一詞將包含包括活性成份及有載劑組成之惰性成份 (醫藥接受性佐藥）之產物，以及任兩種或多種成份或一種或多種成份解離，或由一種或多種成份之其他類反應或作用直接或間接組合、複合或凝集產生之產物。據此，本發明之醫藥組合物包含任一種藉由式I化合物、其他活性成份及醫藥接受性佐藥預混合製成之組合物。對於治療任一種類前列素調節之疾病，式I之化合物可經由口服、吸入噴霧、局部、非腸胃或直腸，依含有一般無毒醫藥接受性載劑、佐藥及載劑之投藥單位調配物投藥。至於本文中所用之非腸胃一詞包含皮下注射、靜脈、肌肉内 '胸骨内注射或注入技術。除治療溫血動物如鼠、老氣、馬、牛、羊、狗、貓等外，本發明之化合物對於人類之治療亦有效。含活性成份之醫藥組合物可為適用口服使用之形式，例 1259080 發明說明續頁 (9) 如錠劑、片粒、藥錠、水溶液或油狀懸浮液、可分散之粉末或細粒、乳液、硬質或軟質膠囊、或糖漿或甘草劑。口服使用之組合物可依據技藝中製造醫藥組合物已知之方法製備，且該組合物可含一種或多種選自由增甜劑、加味劑、調色劑及防腐劑組成之群組之藥劑，以提供醫藥上良好且口未佳之製劑。錠劑含有與適用於製造錠劑之無毒醫藥接受性賦型劑預混合之活性成份。此等賦型劑可為例如惰性稀釋劑如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；顆粒及崩解劑，例如玉米澱粉或藻膠酸；結合劑例如澱粉、明膠或阿拉伯膠，及潤滑劑例如硬脂酸鎂、硬脂酸或滑石。錠劑可未經包衣或可以已知之技術包衣，以延遲腸胃道中之崩解及吸收，且因此提供長期持續之作用。例如，可使用時間延遲物質如單硬脂酸甘油酯或二硬脂酸甘油酯。其亦可以美國專利第4,256,108 ; 4，166,452 ;及4,265,874號中敘述之技術塗佈，形成控制釋出用之滲透治療用錠劑。口服用之調配物亦可以硬質明膠膠囊使用，其中之活性成份係與惰性固態稀釋劑，例如碳酸鈣、磷酸鈣或高嶺土混合，或者軟質明膠膠囊，其中之活性成份係與與水互溶之溶劑如乙二醇、PEG及乙醇，或油性介質如花生油、液態鏈燒或橄欖油混合。水性藏浮液含與適用於製造水性懸浮液之賦型劑預混合之活性物質。該賦型劑為懸浮劑，例如羧基甲基纖維素鈉、甲基纖維素、羥基丙基甲基纖維素、藻酸鈉、聚乙烯基吡咯啶酮、特拉加康斯膠及阿拉伯膠；分散或潤濕劑可為天 14 發明說明續頁 1259080 (10) 然產生之磷脂，例如卵磷脂，或環氧烷與脂肪酸之縮物，例如聚氧基伸乙基硬脂酸酷，或環氧乙燒與長鏈醇之縮合產物，例如十七烷伸乙基氧基十六烷醇，或乙烷與由脂肪酸與己糖醇衍生之部分酯之縮合產物，伸乙基山梨糖醇單油酸酯，或環氧乙烷與由脂肪酸與醇酸酐衍生之部分酯類之縮合產物，例如聚伸乙基山醇酐單油酸酯。水性懸浮液亦可含一種或多種防腐劑如乙基或正丙基對-羥基苯甲酸酯，一種或多種調色劑種或多種加味劑，及一種或多種增甜劑，如蔑糖、糖甜味劑。油狀懸浮亦可藉由使活性成份懸浮於植物油中調配如花生油、橄禮油、芝麻油或椰子油或礦物油如液態韻油狀懸浮亦可含增稠劑，例如蜜壎、硬質鏈燒或十四醇。可添加上述之增甜劑及加味劑以獲得味道佳之口劑。此等組合物可藉由添加抗氧化劑如抗化血酸保存適用於藉由加水製備水性懸浮液之可分散粉末及細使活性成份與分散或潤濕劑、懸浮劍及一種或多種防預混合製備。適用之分散或潤濕劑及懸浮劑已列於上可含其他賦型劑例如增甜劑、加味劑及調色劑。本發明醫藥組合物亦為水包油乳液形式。油相可為油，例如"橄彳覽油或花生油，或礦物油例如液態鏈燒或之混合物。適用之乳化劑可為天然發生之磷脂，例如太卵磷脂，及由脂肪酸及己糖醇酐衍生之酯或部分酯，山梨糖醇酐單油酸酯，及該部分酯與環氧乙烷之縮合產脂肪環氧如聚己糖梨糖，例 1 — 精或，例烷。垸基服製〇粒可腐劑。亦植物此等 .豆、 {列浚口合產 -15 - 1259080 _ (13) 發明說明續頁1259080 Description of invention (5) This is a tautomeric variant. This example may be a ketone of the keto-enol tautomer and its enol form. Individual tautomers and mixtures thereof are included in the compounds of formula I. The compound of formula I can be isolated as a non-stereoisomer pair of enantiomers by, for example, partially crystallizing from a suitable solvent such as methanol or ethyl acetate or mixtures thereof. The enantiomer pairs thus obtained can be separated into individual stereoisomers by conventional means, for example by the use of optically activated acids or bases as solubilizing agents, or by the use of palmar separation techniques such as HPLC separation of the column. Alternatively, the enantiomers of the general compounds of formula I or la can be prepared by stereospecific synthesis using optically pure starting materials or reagents of known structure. "Medicine-acceptable salt" means a salt prepared by a pharmaceutical-receptive non-toxic base (including an inorganic base and an organic base). The salt derived from an inorganic base contains aluminum, ammonium, calcium, copper, iron, menstrual, magnesium, strontium salts. , bell, potassium, sodium, zinc, etc. The best are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutical-receiving organic non-toxic bases contain primary, secondary and tertiary amines, substituted amines Naturally occurring substituted amines, cyclic amines, and organic ion exchange resins such as arginine, beet, caffeine, choline, N, N'-didecylethylenediamine, diethylamine, 2- Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylcridine, glucamine, glucosamine, histidine, halamine (hydrabamine), isopropylamine, 'serine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, pukaine, guanidine, theobromine, triethylamine, trimethylamine, tripropyl Alkylamine, aminobutyric triol, etc. When the compound of the present invention is a base, it can be exemplified by a pharmaceutical containing inorganic acid and an organic acid 1259080. The amount of active ingredient used in combination with a single dosage form will vary with the particular mode of treatment and administration. For example, a human oral pharmaceutical formulation may contain from 0.05 mg to 5 g of a suitable and convenient carrier material ( The active agent may be compounded between about 5 and about 99.95% of the total composition. The dosage unit form will generally contain from about 0.1 mg to about 0.4 g of active ingredient, usually 0.5 mg, i mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 400 mg. Pharmaceutical Compositions Another object of the invention is to provide a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The term "composition" in a composition will include the product of the active ingredient and the inert ingredient of the carrier (medicinal acceptable adjuvant), as well as the dissociation of any two or more ingredients or one or more ingredients, or Or a product produced by directly or indirectly combining, compounding or agglutinating other types of reactions or effects of various components. Accordingly, the pharmaceutical composition of the present invention comprises any of the formulas. A composition prepared by premixing a compound of I, other active ingredients, and a pharmaceutically acceptable adjuvant. For the treatment of any type of prostaglandin-mediated disease, the compound of formula I may be administered orally, by inhalation spray, topically, parenterally or rectally, depending on The administration of a non-toxic pharmaceutical-receiving carrier, an adjuvant, and a carrier is administered as a pharmaceutical formulation. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular intra-sternal injection or injection technique. The compounds of the present invention are also effective for the treatment of humans, such as rats, old air, horses, cows, sheep, dogs, cats, etc. The pharmaceutical composition containing the active ingredient can be in a form suitable for oral use, for example, 1259080 (9) For example, lozenges, granules, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or liquorices. Orally used compositions can be prepared according to methods known in the art for making pharmaceutical compositions, and the compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, toners, and preservatives, Providing a pharmaceutical preparation that is good and has a poor mouth. The tablet contains the active ingredient premixed with a non-toxic pharmaceutically acceptable excipient suitable for use in the manufacture of tablets. Such excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granules and disintegrating agents such as corn starch or alginate; binding agents such as starch, gelatin or gum arabic, And lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a long lasting effect. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The osmotic therapeutic lozenge for controlled release can also be applied by the techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874. Formulations for oral administration can also be used in hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsule, wherein the active ingredient is a solvent which is miscible with water. Ethylene glycol, PEG and ethanol, or an oily medium such as peanut oil, liquid chain burn or olive oil. The aqueous suspension contains an active material premixed with an excipient suitable for use in the manufacture of aqueous suspensions. The excipient is a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragaconsin and gum arabic; Dispersing or wetting agents can be days 14 Description of the invention Continued on page 1259080 (10) The resulting phospholipids, such as lecithin, or a condensation of alkylene oxide and fatty acids, such as polyoxyethylidene stearate, or epoxy a condensation product of ethylene and a long-chain alcohol, such as heptadecane-ethyloxy cetyl alcohol, or a condensation product of ethane with a partial ester derived from a fatty acid and a hexitol, and an ethyl sorbitol mono-oil An ester, or a condensation product of ethylene oxide with a portion of an ester derived from a fatty acid and an alcoholic anhydride, such as a polyethylidene monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more toner species or odorants, and one or more sweeteners such as sucrose, Sugar sweetener. Oily suspensions may also be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil or mineral oils such as liquid rhythm suspensions, such as candied fruit, hard chain burning or Tetradecanol. The above-mentioned sweeteners and odorants may be added to obtain a mouth-feeling agent. These compositions may be preserved by the addition of an anti-oxidant such as antacid acid, a dispersible powder suitable for the preparation of an aqueous suspension by the addition of water, and a finely divided active ingredient with dispersion or wetting agent, suspended sword and one or more pre-mixed preparation. Suitable dispersing or wetting agents and suspending agents are listed above and may contain other excipients such as sweeteners, odorants and toners. The pharmaceutical compositions of the invention are also in the form of an oil-in-water emulsion. The oil phase may be an oil such as " olive oil or peanut oil, or a mineral oil such as a liquid chain or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as too lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, sorbitan monooleate, and the esters and ethylene oxides. Condensation produces a fat epoxy such as polyhexose pear sugar, Example 1 - fine or alkane.垸 based on 〇 granules of preservatives. Also plants, etc. Beans, {Liaokoukou -15 - 1259080 _ (13) Description of the Invention Continued

砂羅美塔唑啉（xylometazoline)、丙基己啶（propylhexedrine)或左旋去氧麻黃驗（levo-desoxyephedrine) ; (7)鎮咳劑包含咳第因（codeine)、氫咳腺（hydrocodone)、卡拉米分（caramiphen)、卡必塔戊烷（carbetapentane)或第塔美瑟分（dextramethorphan) ; (8) 另一種前列腺素配位子’包含前列腺素F拮抗劑，如拉妥普斯特（latanoprost);米縮普特醇（misoprostol)、因普斯替 (enprostil)、理歐普斯替（rioprostil)、摩普特醇（ornoprostol)或羅莎普特醇（rosaprostol) ; (9)粒尿劑；（1〇)非類固醇消炎劑 (NSAIDs)如丙酸衍生物（阿米羅普分（alminoprofen)、苯σ号普分 (benoxaprofen)、巴克稀酸（bucloxic acid)、卡普分（carprofen)、分巴分（fenbufen)、非羅普分（fenoprofen)、佛普分（fluprofen)、佛雙普分（flurbiprofen)、一巴普分（ibuprofen)、Η丨嗓普分 (indoprofen)、酮普分（ketoprofen)、脈羅普分（miroprofen)、拿普山（naproxen)、崎普命（oxaprozin)、峰普分（pirprofen)、般若普分（pranoprofen)、束普分（suprofen)、替普分酸（tiaprofenic acid)及替17号普分（tioxaprofen))、乙酸衍生物（4丨嗓美沙新 (indomethacin)、阿稀美塔新（acemetacin)、阿可分（alclofenac)、梨大内（clidanac)、二可分内（diclofenac)、分可分内（fenclofenac) 、分可酸（fenclozic acid)、分替雜（fentiazac)、服羅分内 (furofenac)、巴分内（ibufenac)、異沙配（isoxepac)、σ号匹内 (oxpinac)'蘇琳打克（sulindac)、替歐皮内（tiopinac)、脫美汀 (tolmetin)、惰美特鋅（zidometacin)及作美克（zomepirac))、分那酸（fenamic acid)衍生物（佛分那酸（flufenamic acid)、美克分那酸（meclofenamic acid)、美分那酸（mefenamic acid)、尼佛酸 -18 - 1259080 發明說明續頁 (14)Xylometazoline, propylhexedrine or levo-desoxyephedrine; (7) antitussives include codeine, hydrocodone, Caramiphen, carbetapentane or dextramethorphan; (8) Another prostaglandin ligand-containing prostaglandin F antagonist, such as lactopast ( Latanoprost); misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; (9) urinary tract (1〇) non-steroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen) ), fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketone Ketoprofen, miroprofen, naproxen, Oxprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen, acetic acid derivatives (4 丨嗓omethaxin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fen Acid (fenclozic acid), fentiazac, furofenac, ibufenac, isoxiepac, oxpinac's ulindac ), tiopinac, tolmetin, zidometacin, and zomepirac, and fenamic acid derivatives (flufenamic acid) ), meclofenamic acid, mefenamic acid, neferic acid -18 - 1259080 Description of the invention (14)

(niflumic acid)及拓分那酸（tolfenamic acid))、雙苯基致酸衍生物（二佛尼酸（diflunisal)及佛分尼酸（flufenisal))、σ号希訊 (oxicams)(異希凱（isoxicam)、匹羅希凱（piroxicam)、蘇惰希凱 (sudoxicam)及添若希凱（tenoxican))，水楊酸鹽（乙酿基水楊酸、硫莎拉 4 (sulfasalazine))及♦峻隆（pyrazolones)(派充 (apazone)、苯旅皮隆（bezpiperylon)、非旅充（feprazone)、莫非保泰松（mofebutazone)、氧基保泰酸（oxyphenbutazone)、苯基保泰松（phenylbutazone)) ; (11)環氧酶-2(COX-2)(cyclooxygenase-2 (COX-2))抑制劑如希雷可希（celecoxib)及羅非可希（rofecoxib) 、陀理可希（etoricoxib)及凡地可希（valdecoxib) ; (12)磷二g旨酶第IV型（PDE-IV)抑制劑例如阿離羅（Ariflo)、羅佛米斯特 (roflumilast) ; (13)化學增活受體之拮抗劑，尤其是CCR-1、 CCR-2及CGR-3 ; (14)膽固醇降低劑如HMG-CoA還原酶抑制劑 (羅發塔ί丁（lovastatin)、新發塔〉’丁（simvastatin)及帕發塔汀 (pravastatin)、佛發塔丁（fluvastatin)、脫發塔 ί丁（atorvastatin)、及其他塔汀（statins))、多價整合劑（贍甾胺（cholestyramine)及可雷替醇（colestipol))、If驗酸、分若纖維酸（fenoHbric acid) 衍生物（間懷薄其（gemfibrozil)、克羅纖維酸酯（clofibrat)、分若纖維酸酯（fenofibrate)及苯并纖維酸酯（benzafibrate))、及普保克醇（probucol) ; (15)抗糖尿劑如胰島素、績醯基尿素、縮二胍（biguanides)(美弗明（metformin))、α-葡糖酶 (a-glucosidase) 抑制劑（阿卡勃（acarbose))及里塔松（glitazones)(troglitazone)、匹里塔松（pioglitazone)、恩里塔松（englitazone)、羅西里塔松 (rosiglitazone)等）；（16)干擾素 β (干擾素 β-la、干擾素 β-lb); -19- 1259080 (16) 發明說明續頁 DMF 二甲基甲醯胺 eq. 當量 Et 乙基 EtO Ac 乙酸乙酯 EtOH 乙醇 HPLC 高壓液相層析 IPA 異丙基醇 IPAc 乙酸異丙酯 Me 甲基 MeOH 甲醇 MHz 兆赫 MTBE 甲基第三丁基醚 NMP - N -甲基-2 - ^比p各咬嗣 NMR 核磁共振 THF 四氫呋喃 TLC 薄膜層析(niflumic acid) and tolfenamic acid, diphenyl acid derivatives (diflunisal and flufenisal), σ oxicams (isocams) Isoxicam, piroxicam, sudoxicam, and tenoxican, salicylate (sulfosalazine, sulfasalazine) and ♦ Pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone) Phenylbutazone)); (11) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib, rhodamine (etoricoxib) and valdecoxib; (12) PDE-IV inhibitors such as Ariflo and roflumilast; (13) Antagonists of chemically active receptors, especially CCR-1, CCR-2 and CGR-3; (14) Cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, new hair tower) >'Ding (simvastatin) and pravastatin, fluvastatin, atorvastatin, and other statins, multivalent integrators (cholestyramine) Colestipol, If acid, FenoHbric acid derivatives (gemfibrozil, clofibrat, fenofibrate, and benzene) And benzafibrate, and probucol; (15) antidiabetic agents such as insulin, sulphonyl urea, biguanides (metformin), alpha-glucos A-glucosidase inhibitors (acarbose) and glitazones (troglitazone), pioglitazone, englitazone, rosiglitazone (16) interferon beta (interferon beta-la, interferon beta-lb); -19- 1259080 (16) description of the invention continuation page DMF dimethylformamide eq. equivalent Et ethyl EtO Ac Ethyl acetate EtOH ethanol HPLC high pressure liquid chromatography IPA isopropyl alcohol IPAc isopropyl acetate Me Group MeOH Methanol MHz megahertz MTBE methyl tert-butyl ether NMP - N - methyl - 2 - p ^ each bite ratio Si NMR nuclear magnetic resonance THF tetrahydrofuran TLC thin-layer chromatography

合成方法本發明之式I化合物可依據反應圖1至5中所列之反應路徑且遵循本文中所述之方法製備。式IV之中間物化合物可以反應圖1所示之方法，由適用之經取代苯基聯胺II製備。II與適用之環烷酮III (其中R為酯基如烷基）在Fisher^哚或類似條件下反應，獲得IV。反應圖1 -21 - 1259080 發明說明續頁Synthetic Methods The compounds of formula I of the present invention can be prepared according to the reaction schemes listed in Schemes 1 through 5 and following the procedures described herein. The intermediate compound of formula IV can be prepared by the method shown in Figure 1 from a suitable substituted phenyl hydrazine II. II is reacted with a suitable cycloalkanone III (wherein R is an ester group such as an alkyl group) under Fisher® or the like to obtain IV. Reaction diagram 1 - 21 - 1259080 Description of the invention

(Π) 式IV之化合物可另外藉由反應圖2所示之方法，由適用之經取代苯胺V製備。V與適用之環烷酮III縮合，接著在Heck 或類似之金屬催化條件下環化，獲得啕哚IV。(Π) The compound of the formula IV can be additionally prepared from the applicable substituted aniline V by the method shown in the reaction scheme of Fig. 2. V is condensed with a suitable cycloalkanone III and then cyclized under Heck or similar metal catalyzed conditions to obtain oxime IV.

反應圖2 〇Reaction Figure 2 〇

式III之化合物可以反應圖3中所示之方法，甴適用之經取代矽烷基晞醇醚VI或適用之婦胺VII製備。在鹼如烷基鋰或路易斯酸如三氟乙酸銀之存在下，使適當之親電子（如 Y-CH2C〇2R (其中Y代表鹵素或離去基）與矽烷基晞醇醚VI加成，獲得環烷酮III。式III之化合物可另外在Stork烯胺或類似條件下，將Y-CH2C02R添加於適用之經取代烯胺VII上製備。反應圖3 - -22 - 1259080 _ (18) 發明說明續頁The compound of formula III can be prepared by the method shown in Figure 3, using a substituted indole sterol ether VI or a suitable gynecamine VII. Appropriate electrophiles (such as Y-CH2C〇2R (where Y represents a halogen or a leaving group) are added to the indenyl sterol ether VI in the presence of a base such as an alkyl lithium or a Lewis acid such as silver trifluoroacetate, Obtaining a cycloalkanone III. The compound of formula III can be additionally prepared by adding Y-CH2C02R to a suitable substituted enamine VII under a Stork enamine or the like. Reaction Scheme 3 - -22 - 1259080 _ (18) Invention Description continuation page

OTMSOTMS

1· Y-CH2C〇2R 2· H2〇 C02R1· Y-CH2C〇2R 2· H2〇 C02R

式VIII之中間物化合物可由反應圖4中所示之方法，由適當之經取代吲哚IV製備。IV之溴化可以溴或溴化劑如三溴化说淀，在驗性條件下，於極性溶劑中達成，如在p比咬或溶劑如二氯甲烷中，在酸及還原金屬之條件下進行，產生溴啕哚VIII。反應圖4The intermediate compound of formula VIII can be prepared from the corresponding substituted oxime IV by the method shown in Figure 4 of the reaction scheme. The bromination of IV can be achieved by bromine or a brominating agent such as tribromination, under the conditions of the test, in a polar solvent, such as in p-biting or solvent such as dichloromethane, under the conditions of acid and reducing metal. This is carried out to produce bromoquinone VIII. Reaction Figure 4

1. Br2, pyridine 2. Metal, acid (IV)1. Br2, pyridine 2. Metal, acid (IV)

(VIII)(VIII)

式I之化合物可以反應圖5中所示之方法，由適用之經取代溴吲哚VIII製備。以適用之親電子如（RiMRJCH-Y在鹼存在下，於適用溶劑如DMF中使VIII烷化，獲得N-烷化之4哚 IX。使IX與甲烷磺酸鹽如甲烷磺酸鈉在Cu(I)鹽中偶合，獲得式I之化合物，接著使酯水解。溴啕哚酸（IX，R=H)另外可先與適用'之金屬化劑如n-BuLi反應，接著抓取親電子基如甲基二硫醚，獲得相對應之甲基硫醚，當以例如過氧化氫/鎢酸鈉氧化時，獲得化合物IA。使溴啕哚VIII烷化接著磺醯化之步驟亦可逆向進行；因此使溴蚓哚VIII磺醯化獲得化合物 -23 - (19) 1259080 χ，其係使用上述類似之條件，式IA之化合物’接著使酯水解反應圖5The compound of formula I can be prepared by reacting the substituted bromoquinone VIII by the method shown in Figure 5. Alkylation of VIII with a suitable electrophile such as (RiMRJCH-Y in the presence of a base in a suitable solvent such as DMF to give N-alkylated 4哚 IX. IX with methanesulfonate such as sodium methanesulfonate in Cu (I) coupling in a salt to obtain a compound of formula I, followed by hydrolysis of the ester. Bromodecanoic acid (IX, R = H) may additionally be reacted with a suitable metallizing agent such as n-BuLi, followed by capture of the electrophile For example, methyl disulfide, the corresponding methyl sulfide is obtained, and when it is oxidized, for example, with hydrogen peroxide/sodium tungstate, the compound IA is obtained. The step of alkylating bromine VIII followed by sulfonation can also be reversed. Thus; sulfonium VIII is sulfonated to give the compound -23 - (19) 1259080 oxime, using a similar condition as described above, the compound of the formula IA' is followed by hydrolysis of the ester.

C〇2R Y-CH(R1)(R2)f base; hydrolysis orC〇2R Y-CH(R1)(R2)f base; hydrolysis or

Mitsunobu conditions with R1R2CH0H 發明說明續頁或使用反應條件淀化，獲得Mitsunobu conditions with R1R2CH0H Description of the invention Continued or by precipitation using reaction conditions

CO^R Y-CHfRWFy，baseCO^R Y-CHfRWFy,base

c〇2rC〇2r

Cul，CH^SOsNa or similar conditions; hydrolysis or with R=Hf BuLi; MeSSMe;H202/Na2W〇4Cul, CH^SOsNa or similar conditions; hydrolysis or with R=Hf BuLi; MeSSMe; H202/Na2W〇4

CO〇H 化合物IB可甴唾保確少τ a ,. ” 田、，·二保4《U ,例如IA之酯，藉甴使用適氧化劑氧化，接著7jc M# 丄=十香KI備，如反應圖ό中之說明。反應圖6CO〇H Compound IB can be surely less τ a ,. ” Tian,,··二保4 “U, such as IA ester, by oxidizing with suitable oxidizing agent, then 7jc M# 丄= 十香 KI, such as Description of the reaction diagram 反应 Reaction Figure 6

-24- 1259080 _ (23) 發明說明續頁隔夜且供以水。次日早晨，以酮胺（1 〇-1 5毫克/ kg i.m.)使動物鎮靜，接著移掉其牢籠。將其置於加熱之檯（36。(：）上，且注射劑量（5-12毫克/kg i.v.)之propofol。該動物插入氣管内管 (4-6毫米I.D·)，且持續靜脈注射propofol (25-30毫克/公斤/小時）保持麻醉。全部實驗過程中監控其生命跡象（心跳速率’血壓、呼吸速率、體溫）。鼻塞之測量：動物呼吸阻塞之測量係經由與氣管相連之氣動速度計獲取，以確保其為正常。使用Ec〇visi〇n accoustic rhinometer以評估鼻塞。該技術提供鼻部内部之非侵入性2D 回聲。沿著鼻腔長度之鼻部體積及最小截面積在秒内以安裝客製化軟體之（Hood Laboratories，Mass，U.S.A·)之膝上型電腦計算。鼻部之刺激直接由動物之鼻腔（5 0微升體積）釋出。在之前及刺激60-120分鐘後紀錄鼻塞之變化。若發生鼻塞，則或使鼻腔之體積下降。星刻練之清醒松鼠猴之肺部力學域驗程序包含將經訓練之松鼠猴置於暴露氣溶膠之室之椅上。為對照用，因此約30分鐘紀錄一次呼吸參數之肺部力學測量’以建互遠天各猴子之一般對照值。針對口服投藥，係將化合物以1%甲醇溶液溶解或懸浮（甲基纖維素， 65HG，400 cps)，且以1毫升/公斤體重之體積投藥。針對化合物之氣溶膠投藥，係使用DeV仙iss超音波噴霧器。預治療時間在猴子以PGD2或Ascaris suum抗原；1 : 25稀釋刺激前，由5分鐘至4小時變化。刺激後，以電腦計算各分鐘之數據，以各呼吸參數（包冬 1259080 _ (24) 發明說明續頁-24- 1259080 _ (23) Description of Invention Continued Page Overnight and supplied with water. The next morning, the animal was sedated with ketoamine (1 〇 -1 5 mg / kg i.m.), and then the cage was removed. Place it on a heating table (36. (:), and inject the dose (5-12 mg / kg iv) of propofol. The animal is inserted into the endotracheal tube (4-6 mm ID·), and continuous intravenous propofol (25-30 mg/kg/hr) maintained anesthesia. All signs of life (heart rate, blood pressure, respiration rate, body temperature) were monitored during the course of the experiment. Measurement of nasal congestion: Measurement of respiratory obstruction in animals is via pneumatic speed connected to the trachea Obtained to ensure that it is normal. Use the Ec〇visi〇n accoustic rhinometer to assess nasal congestion. This technique provides a non-invasive 2D echo inside the nose. The nasal volume along the length of the nasal cavity and the smallest cross-sectional area are within seconds. The computerized version of the custom software (Hood Laboratories, Mass, USA) was installed. The nasal stimulation was directly released from the nasal cavity of the animal (50 microliter volume). Before and after 60-120 minutes of stimulation Record changes in nasal congestion. If nasal congestion occurs, or reduce the volume of the nasal cavity. The lung mechanics test procedure of the singular squirrel monkey includes the placement of the trained squirrel monkey in the chamber exposed to aerosol. On the chair. For comparison, the lung mechanics measurement of respiratory parameters is recorded in about 30 minutes to establish the general control value of each monkey in the distant days. For oral administration, the compound is dissolved or suspended in 1% methanol solution (A Cellulose, 65HG, 400 cps), and is administered in a volume of 1 ml / kg body weight. For aerosol administration of compounds, DeV Xianiss ultrasonic spray is used. Pretreatment time in monkeys with PGD2 or Ascaris suum antigen; : 25 dilution before stimulation, from 5 minutes to 4 hours. After stimulation, calculate the data of each minute by computer, with each breathing parameter (Baodong 1259080 _ (24) Invention Description Continued

鼻腔阻抗（RL)及動態之平順（Cdyn))與對照值之百分比改變。針對刺激60分鐘後之最小時段依序獲得各試驗化合物之結果，接著與先前獲得之該猴基準對照值比較。另外，分別平均各猴刺激後60分鐘之全部值（過去之基準值及試驗值），且用於計算調節劑或試驗化合物之Ascaris抗原反應。針對統計分析，係使用成對之卜試驗（參考·· McFadane， C.S.等人，Prostaglandins，28，173-1 82 ( 1984)及 McFarlane，C.S. 等人，Agents Actions, 22，63-68 ( 1987))。過敏之羊引發性去氣管阻塞之預防_ 動物準備：使用平均重量35公斤（18至50公斤）之成羊。使用之所有動物均符合二標準· a)對Ascaris suum萃取液（Greer Diagnostics，Lenois，NC)之 1 : 1000或 1 : 1〇〇〇〇稀釋均具有自然之皮膚反應；及b)其對於具有急性支氣管阻塞及後期之支氣管阻塞之Ascaris smim之吸入性刺激（W M Abraham et al.， Am· Rev. Resp. Dis·，128, 839-44 ( 1983))均會預先反應。The percentage of nasal impedance (RL) and dynamic smoothness (Cdyn) was changed from the control value. The results of each test compound were sequentially obtained for the minimum time period after 60 minutes of stimulation, and then compared with the previously obtained monkey reference control value. In addition, all values (past values and test values) of 60 minutes after each monkey stimulation were averaged and used to calculate the Ascaris antigen response of the modulator or test compound. For statistical analysis, a paired test is used (cf. McFadane, CS et al., Prostaglandins, 28, 173-1 82 (1984) and McFarlane, CS et al., Agents Actions, 22, 63-68 (1987). ). Prevention of allergic sheep-induced devascularization - Animal preparation: Use an average weight of 35 kg (18 to 50 kg) of sheep. All animals used met the second standard. a) 1 : 1000 or 1:1 dilution of Ascaris suum extract (Greer Diagnostics, Lenois, NC) has a natural skin reaction; and b) it has The inhalational stimuli of Ascaris smim (WM Abraham et al., Am. Rev. Resp. Dis., 128, 839-44 (1983)) for acute bronchial obstruction and later bronchial obstruction are pre-reactive.

呼吸動力學之測量：使為刺激之羊置於與其頭部移動成傾斜位置《牢籠中。鼻腔以2%里朵卡因（Hd〇caine)溶液局部麻醉後’使球狀導管經一鼻孔進入下方食道中。接著經過另一鼻孔，使用可撓纖維支氣管视管引導，對動物插入氣官内管。以食运球狀導管（无填—亳升空氣）計算胸腔壓力，其係經配置，使吸氣產生可明顯識別心臟振動之負偏恩。氣管之側向塵力係以前進通過且使其末端在鼻管.端之側孔導管（内徑2·5毫米）測量。肺部傳輸壓力（導管壓力及胸膜塵力間之差異）係以差分壓力轉換器（DP45; Valldyne -29< 1259080 (25) 發明說明續頁Measurement of Respiratory Dynamics: Place the stimulating sheep in a tilted position with its head moved into a cage. After the nasal cavity was locally anesthetized with 2% drocaine (Hd〇caine) solution, the spherical catheter was passed through a nostril into the lower esophagus. The animal is then inserted into the gastrointestinal tube through another nostril, guided by a flexible fiberoptic bronchial tube. The thoracic pressure is calculated by the food-ball-shaped catheter (no filling-swelling air), which is configured such that the inhalation produces a negative bias that clearly identifies the heart's vibration. The lateral dust force of the trachea was measured by advancing through and passing the end of the trachea at the end of the nasal cannula (inner diameter 2·5 mm). Pulmonary transmission pressure (difference between catheter pressure and pleural dust) is a differential pressure transducer (DP45; Valldyne -29 < 1259080 (25)

Corp.，Northridge, CA)測量。對於肺部阻抗（Rl)之測f ’鼻管之最終端係與氣動速度計（Fleisch, Dyna Sciences, Blue Bell， PA)相通。於示波器（Model DR-12; Electronics for Medicine，White Plains，NY)上紀錄流動及肺部傳輸壓力，其係與PDP-Π數位電月鐘（Digital Equipment Corp·，Maynard，MA)相連，連線計异肺部傳輸壓力之RL、整體獲得之呼吸體積及流動。使用10-15 次呼吸測定RL。胸部氣體體積（Vtg)係於身體體積變化描繪器測量，以獲得特定之肺部阻抗（SRL =R，Vtg)。下列實例係用於說明本發明，且不依任何方式限制本發明之範圍。實例中，除非另有說明，一所有式I之最終化合物均以NMR、TLC及質譜之元素分析分析； —中間物係以NMR及TLC分析；一大部分化合物均在碎膠上以快速層析分析，再結晶及/或懸浮過濾（懸浮於溶劑中，接著過濾固體）； —反應過程係以薄層層析（TLC)追蹤及反應時間僅用於說明； —對映體過量係在普通相HPLC上以對掌性管柱：ChiralPak AD ; 250 X4.6毫米測量。下列中間物係依據文獻程序製備或購自下列供應商： 2-(2-氧代-環戊基）乙故乙自旨：Acros/Fisher Scientific。 4-象-2-硤苯胺：Beugelmans，R.; Chbani，M. Bull· Soc. Chim· Fr. 1995, 132, 306-3 13 o 實例1 -30- 1259080 (26) 發明說明續頁 (-)-[4-(4-氯芊基）-7-氟-5-(甲烷磺醯基）-1，2,3,4-四氫環戊并[b]Corp., Northridge, CA). For the measurement of lung impedance (Rl), the end of the nasal tube is connected to a pneumatic speedometer (Fleisch, Dyna Sciences, Blue Bell, PA). Flow and lung transmission pressures were recorded on an oscilloscope (Model DR-12; Electronics for Medicine, White Plains, NY) connected to a PDP-Π Digital Electric Equipment (Dayly Equipment Corp., Maynard, MA) The RL of the transmission pressure of the lungs, the respiratory volume and flow obtained overall. The RL is measured using 10-15 breaths. The chest gas volume (Vtg) is measured by the body volume change plotter to obtain a specific lung impedance (SRL = R, Vtg). The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way. In the examples, all the final compounds of formula I were analyzed by elemental analysis of NMR, TLC and mass spectrometry unless otherwise stated; - the intermediates were analyzed by NMR and TLC; a large part of the compounds were flash chromatographed on the gel. Analysis, recrystallization and/or suspension filtration (suspended in solvent, followed by filtration of solids); - reaction process is traced by thin layer chromatography (TLC) and reaction time is for illustration only; - enantiomeric excess is in common phase HPLC was performed on a palm tube: ChiralPak AD; 250 X 4.6 mm. The following intermediates were prepared according to literature procedures or purchased from the following suppliers: 2-(2-oxo-cyclopentyl) Ethylene B: Acros/Fisher Scientific. 4-like-2-indole aniline: Beugelmans, R.; Chbani, M. Bull·Soc. Chim· Fr. 1995, 132, 306-3 13 o Example 1 -30- 1259080 (26) Description of the invention (- )-[4-(4-chloroindolyl)-7-fluoro-5-(methanesulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]

步驟1 : ( + /-Η 7-氟-1，2,3,4-四氫環戊并[bp?丨哚-3-基）乙酸乙酯Step 1: ( + /-Η 7-fluoro-1,2,3,4-tetrahydrocyclopenta[bp?indol-3-yl)acetate

CO〇Et 在N2下，以Dean-Stark畔使含10.00克4-氟-2-破苯胺、6.57克 2-(2-氧代環戊基）乙酸乙酯及121克對-甲苯磺酸之100毫升苯溶液回流24小時。隨後，蒸館移除苯。接著，添加60毫升 DMF，且於溶液除氣後依序添加19毫升Hunig驗及405毫克 Pd(0Ac)2。溶液加熱至115°C 3小時，接著冷卻至室溫。為終止反應，因此添加300毫升IN HC1及200毫升乙酸乙酯，且使混合物經矽藻土過濾。使相分離且以200毫升乙酸乙酯萃取酸性相二次。合併有機相，以食鹽水洗滌，以無水Na2S04 脫水，經矽藻土過濾且濃縮。粗物質以快速層析，以100% 甲苯溶離進一步純化，獲得5.36克黃色固態標題化合物。 lH NMR C丙酮-d6) δ 9.76 (br s，1H)，7.34 (dd，1H)，7.03 (d，1H)， 6.78 (td, 1H), 4. 14 (q, 2H)? 3.57 (m, 1H)? 2.85-2.55 (m, 5H), 2.15 (m, 1H)，1.22 (t，3H)。步驟2 : ( + /-)-(7-氟-1，2,3,4-四氫環戊并[13]啕哚-3-基）乙酸 -31 - 1259080 發明說明續頁CO〇Et Under N2, 10.00 g of 4-fluoro-2-resorpene, 6.57 g of 2-(2-oxocyclopentyl)acetate and 121 g of p-toluenesulfonic acid were added as Dean-Stark. 100 ml of benzene solution was refluxed for 24 hours. Subsequently, the steaming hall removes benzene. Next, 60 ml of DMF was added, and after the solution was degassed, 19 ml of Hunig and 405 mg of Pd(0Ac)2 were sequentially added. The solution was heated to 115 ° C for 3 hours and then cooled to room temperature. In order to terminate the reaction, 300 ml of IN HC1 and 200 ml of ethyl acetate were added, and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 mL of ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na. The crude material was purified by flash chromatography eluting with EtOAc EtOAc lH NMR C-acetone-d6) δ 9.76 (br s,1H), 7.34 (dd,1H), 7.03 (d,1H), 6.78 (td, 1H), 4. 14 (q, 2H)? 3.57 (m, 1H)? 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H). Step 2: ( + /-)-(7-Fluoro-1,2,3,4-tetrahydrocyclopenta[13]indol-3-yl)acetic acid -31 - 1259080

co2h 在室溫下，於含丨·24克步驟1之酷之14毫升四氫呋喃（THF) 溶液中添加7毫升甲醇，接著添加7毫升2N Na〇H。2.5小時後，將反應混合物倒入含乙酸乙醋（Et0Ac)nN HC1之分液漏斗中。使相分離，且以EtOAc萃取酸性相二次。合併有機相’ 以食鹽水洗滌，以無水Na2S〇4脫水且蒸發至乾’獲得8克粗且不安定之躐狀棕色油狀物’其以該狀態用於下一步驟中（純度>90%)。 4 NMR (丙酮-d6) δ 10.90 (br s，1H)，9.77 (br s，1H)，7.34 (dd， 1H)，7.04 (dd，1H) 6.79 (td，1H)，3.56 (m，1H)，2·90-2,50 (m，5H)， 2.16 (m，1H)。MS (-APCI) m/z 232·2 (M-H)。步驟3:( + /-)-(5-溴-7-氟-1，2,3,4-四氫環戊并1>]啕哚-3-基）乙酸Co2h 7 ml of methanol was added to a solution of ruthenium 24 g of 14 ml of tetrahydrofuran (THF) at room temperature, followed by the addition of 7 ml of 2N Na〇H. After 2.5 hours, the reaction mixture was poured into a seperate containing ethyl acetate (Et0Ac) nN HCl. The phases were separated and the acidic phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na.sub.2.sub.4 and evaporated to dryness to afford <RTI ID=0.0>>&&&&&&&&&&&&&&&& %). 4 NMR (Acetone-d6) δ 10.90 (br s, 1H), 9.77 (br s, 1H), 7.34 (dd, 1H), 7.04 (dd, 1H) 6.79 (td, 1H), 3.56 (m, 1H) , 2.90-2, 50 (m, 5H), 2.16 (m, 1H). MS (-APCI) m/z 232·2 (M-H). Step 3: (+ /-)-(5-bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta-1)]indol-3-yl)acetic acid

在-40。(：下，於含2.20克步驟2之酸（純度>90%)之30毫升17比啶溶液中添加6.85克三溴化吡啶（純度90%)。懸浮液於0°(：下攪摔10分鐘，且升溫至室溫30分鐘。接著在高度真空中未加熱下移除溶劑。粗物質溶於40毫升Ac〇H中，且在0。(：下將 2.88克Zn逐份添加於冷卻之溶液中。使懸浮液在15°C下攪捽 15分鐘，且升溫至室溫再15分鐘。此時，添加IN HCI終止反應，且將該混合物倒入含食鹽水/EtOAc之分液漏斗中。使層 -32 - 1259080 發明說明續頁 (28) 分離，且以水、食鹽水洗）條有機層，以無水Na2S〇4脫水且濃縮。該物質未進一步純化用於下一步驟。 NMR (丙酮-d6) δ 10.77 (br s，1H)，9.84 (br s, 1H)，7.09 (m， 2H), 3.60 (m，1H)，2.95-2.65 (m, 4H)，2.56 (dd, 1H)，2.19 (m, 1H)。步驟4 : ( + /-)-[5-溴-4-(4-氯芊基）-7-氟-1,2,3,4-四氫環戊并[b] 吲哚-3-基]乙酸At -40. (: Next, add 6.85 g of pyridine tribromide (purity 90%) to a 30 ml 17-pyridine solution containing 2.20 g of the acid of Step 2 (purity > 90%). The suspension was stirred at 0 ° (: 10 minutes, and warmed to room temperature for 30 minutes. Then remove the solvent without heating under high vacuum. The crude material was dissolved in 40 ml of Ac〇H, and at 0: 2.8 g of Zn was added portionwise to the cooling. In the solution, the suspension was stirred at 15 ° C for 15 minutes and warmed to room temperature for another 15 minutes. At this time, the reaction was quenched by the addition of IN HCI and the mixture was poured into a sep. Intermediate layer: 32- 1259080 Description of the invention (28) Separation, and washing with water and brine, the organic layer was dried over anhydrous Na.sub. Acetone-d6) δ 10.77 (br s,1H), 9.84 (br s, 1H), 7.09 (m, 2H), 3.60 (m,1H), 2.95-2.65 (m, 4H), 2.56 (dd, 1H) , 2.19 (m, 1H). Step 4: ( + /-)-[5-Bromo-4-(4-chloroindolyl)-7-fluoro-1,2,3,4-tetrahydrocyclopenta[ b] ind-3-yl]acetic acid

於含2.13克步驟3之酸之10毫升THF溶液中過量添加含重氮甲烷之乙醚溶液，直到以TLC監控之酸完全消耗為止。接著，真空移除溶劑。在-78t：下，於含因此形成之粗甲酯之 20毫升DMF溶液中添加539毫克NaH懸浮液（油中60%)。使懸浮液於〇°C下攪拌10分鐘，再次冷卻至-78°C，且以1.70克4-氯芊基溴處理。5分鐘後，使溫度升溫至0°C，且使混合物攪拌20分鐘。此時，添加2毫升AcOH終止反應，且將該混合物倒入含IN HCl/Et〇Ac之分液漏斗中。使層分離且以食鹽水洗條有機層，以無水Na2S〇4水且濃縮。使用步驟2中所述之程序使烷化之物質水解。粗物質分散於EtOAc/己烷中進一步純化，得2.35克淡棕色固態標題化合物。 NMR (丙酮-d6) δ 10.70 (br s，1H)，7.31 (d，2H)，7.18 (d，1H)， 7.06 (d, 1H), 6.92 (d, 2H), 5.90 (d, 1H)? 5.74 (d, 1H), 3.61 (m, 1H), 3.00-2.70 (m, 3H), 2.65 (dd，1H)，2.39 (dd, 1H), 2.26 (m，1H)。MS (-APCI) m/z 436.3, 434.5 (M-HV。 -33 ^ 1259080 _____ (29) 發明說明續頁步‘驟5 : ( + )-[5-溴-4-(4-氯芊基）-7-氟-1，2,3,4-四氫環戊幷[b]吲嗓-3-基]乙酸The diethyl ether solution containing diazomethane was added in excess to a solution of 2.13 g of the acid from step 3 in 10 ml of THF until the acid was completely consumed by TLC. The solvent is then removed in vacuo. A solution of 539 mg of NaH (60% in oil) was added to a solution of the crude methyl ester thus formed in 20 ml of DMF at -78t. The suspension was stirred at 〇 ° C for 10 minutes, cooled again to -78 ° C, and treated with 1.70 g of 4-chloroindenyl bromide. After 5 minutes, the temperature was raised to 0 ° C and the mixture was stirred for 20 minutes. At this time, the reaction was quenched by the addition of 2 ml of AcOH, and the mixture was poured into a sep. funnel containing &lt The layers were separated and the organic layer was washed with brine, dried over anhydrous Na? The alkylated material is hydrolyzed using the procedure described in Step 2. The crude material was taken up in EtOAc / EtOAc (EtOAc) NMR (Acetone-d6) δ 10.70 (br s, 1H), 7.31 (d, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 5.90 (d, 1H)? 5.74 (d, 1H), 3.61 (m, 1H), 3.00-2.70 (m, 3H), 2.65 (dd, 1H), 2.39 (dd, 1H), 2.26 (m, 1H). MS (-APCI) m/z 436.3, 434.5 (M-HV. -33^1259080 _____ (29) Description of the invention Continued Page Step 5: ( + )-[5-Bromo-4-(4-chloroindolyl) )-7-fluoro-1,2,3,4-tetrahydrocyclopentanyl [b]indol-3-yl]acetic acid

在80。(：下，於含2.35克步驟4之酸之130毫升EtOH中添加780 微升（S) -(·) -1 -( 1 -莕基）乙胺。使溶液冷卻至室溫且攪拌隔夜。回收之鹽（1.7克）以200毫升EtOH再度再結晶。過濾後，所得白色固態鹽以IN HC1中和’且以EtOAc牟取產物。有機層以食鹽水洗滌，以無水Na2S〇4脫水且濃縮。物質於Si〇2 整上以EtOAc溶離過濾，獲得500毫克白色固態標題對映體。二對映體之駐留時間分別為7·5分鐘及9·4分鐘[ChiralPak AD 管柱，己烷/2-丙醇/乙酸（95 : 5 ·· 0·1)]。更極性之對映體為 98% ee。ee=98% ;駐留時間=9.4分鐘[ChiralPak AD管柱：250 Χ4·6毫米，己烷 /2-丙醇 / 乙酸（75:25:0.1)]; [α]〇21= +39·2。（c MeOH)。步驟6 : (-)-[4-(4-氯芊基氟甲板績醯基）-1，2,3,4-四氫環戊并[b；H丨哚-3-基]乙酸及納鹽先以重氮甲烷使步驟5之酸（15‘4克）醋化。續酿化係藉由使因此形成之酯與16.3克甲纪績酸納鹽及30.2克CuI昆合於N-甲；吡咯啶酮中達成。懸浮液於心流中除氣，加熱至 1 5 0。(：且攪摔3小時，接著冷卻至室溫。為使反應終止，因此添加500毫升乙酸乙酯及500毫升己燒’且使混合物經Si〇2 墊，以EtOAc溶離過濾。濃縮有機相。粗油以Et0Ac溶解， '34- 1259080 (30) 發明說明續頁以水洗務三次且以食鹽水洗；條一次，以無水Na2S04脫水，經過濾且濃縮。粗物質再以100%甲苯至50%甲苯/EtOAc之梯度溶離之快速層析純化，獲得14克磺化之酯，其使用步驟2所述之程序水解。經下列二次持續再結晶後獲得白色固態標題化合物（9.8克）：乙酸異丙酯/庚烷，接著CH2C12/己烷。咕 NMR (500 MHz，丙酮-d6) δ 10.73 (br s, 1H)，7.57 (d，2H，J=8.8 Hz)，7.31 (m，1H)，7·29 (m，1H)，6.84 (d，2H，J=8.8 Hz)，6.29 (d， 1H，JAB=17.8 Hz)，5,79 (d，1H，JAB=17.8 Hz)，3.43 (m，1H)，2.98 (s， 3H)，2.94 (m，1H)，2.85-2.65 (m，3H), 2.42 (dd，1H，Hz，J2= 10.3 Hz)，2.27 (m, 1H)。13C NMR (125 MHz 丙酮-d6) δ 173.0, 156.5 (d，JCF=237 Hz)，153.9, 139.2, 133.7, 133·3, 130.0 (d，JCF= 8.9 Hz)，129.6，128.2，127.5 (d，JCF=7.6 Hz)，122.2 (d，Jcf:4·2 Hz)， 112.3 (d，JCF=29‘4 Hz)，lll_〇 (d，JCF=22.6 Hz)，50.8，44.7，38.6, 36.6，36.5, 23,3。MS 〇APCI) m/z 436.1，434.1 (Μ·Η)-。 ee=97% ;駐留時間 15·3分鐘[Chil:aiCel OD管柱：250 X 4.6毫米，己烷 /2-丙醇 / 乙醇 / 乙酸（90:5:5:0.2)] ; [cc]D21 = -29.3。（c 1.0, Me〇H)。At 80. (: Next, 780 μl of (S)-(·)-1 -(1-indolyl)ethylamine was added to 130 ml of EtOH containing 2.35 g of the acid of Step 4. The solution was allowed to cool to room temperature and stirred overnight. The recovered salt (1.7 g) was recrystallized from EtOAc (EtOAc) (EtOAc). The material was filtered over EtOAc (EtOAc) eluted eluted eluted eluted eluted eluted eluted eluted -propanol/acetic acid (95:5 ··0·1)]. The more polar enantiomer is 98% ee. ee=98%; residence time = 9.4 minutes [ChiralPak AD column: 250 Χ 4·6 mm, Hexane/2-propanol/acetic acid (75:25:0.1)]; [α]〇21= +39·2 (c MeOH) Step 6: (-)-[4-(4-chloroindenyl) Fluoride Deck) -1,2,3,4-tetrahydrocyclopenta[b;H丨哚-3-yl]acetic acid and sodium salt first acid (15'4 g) in step 5 with diazomethane ) vinegarization. Continued brewing by making the ester thus formed with 16.3 g of methicillin sodium salt and 30.2 CuI is combined with N-methyl; pyrrolidone. The suspension is degassed in the heart flow, heated to 150. (: and stirred for 3 hours, then cooled to room temperature. In order to terminate the reaction, therefore added 500 ml of ethyl acetate and 500 ml of hexanes were added and the mixture was passed through a pad of EtOAc (EtOAc) eluted eluted with EtOAc. The organic phase was concentrated. The crude oil was dissolved in Et0Ac, '34- 1259080 (30) The mixture was washed with brine; the mixture was dried with anhydrous Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography eluting with 100% toluene to 50% toluene/EtOAc to give 14 g of sulfonated ester. Hydrolysis of the procedure described in Step 2. The title compound (9.8 g) was obtained as a white solid: EtOAc EtOAc EtOAc (EtOAc) δ 10.73 (br s, 1H), 7.57 (d, 2H, J = 8.8 Hz), 7.31 (m, 1H), 7·29 (m, 1H), 6.84 (d, 2H, J = 8.8 Hz), 6.29 (d, 1H, JAB=17.8 Hz), 5,79 (d, 1H, JAB=17.8 Hz), 3.43 (m, 1H), 2.98 (s, 3H), 2.94 (m, 1H), 2.85-2.65 ( m, 3H), 2.4 2 (dd, 1H, Hz, J2 = 10.3 Hz), 2.27 (m, 1H). 13C NMR (125 MHz acetone-d6) δ 173.0, 156.5 (d, JCF = 237 Hz), 153.9, 139.2, 133.7, 133·3, 130.0 (d, JCF = 8.9 Hz), 129.6, 128.2, 127.5 (d, JCF=7.6 Hz), 122.2 (d, Jcf: 4·2 Hz), 112.3 (d, JCF=29'4 Hz), lll_〇(d, JCF=22.6 Hz), 50.8, 44.7, 38.6, 36.6, 36.5, 23, 3. MS 〇 APCI) m/z 436.1, 434.1 (Μ·Η)-. Ee=97%; residence time 15.3 minutes [Chil: aiCel OD column: 250 X 4.6 mm, hexane/2-propanol / ethanol / acetic acid (90:5:5:0.2)]; [cc]D21 = -29.3. (c 1.0, Me〇H).

Mp 175.0°C 〇鈉鹽係藉由在EtOH (100毫升）中，以14.80毫升IN NaOH水溶液處理6·45克（14.80毫莫耳）之上述酸化合物製備。真空移除有機溶―劑，且在回流下將粗固體溶於1.2升異丙醇中。以蒸餾溶劑使最終之體積下降至500毫升。冷卻至室溫結晶鈉鹽。將結晶之鈉鹽懸浮於Η20中，以乾冰浴冷凍且高度真空凍乾，獲得6.00克標題化合物之鈉鹽。 -35 - 1259080 發明說明續頁 (31) lH NMR ( 500 MHz, DMSO-d6) δ 7.63 (dd, 1H, 8.5 Hz, J2=2.6Mp 175.0 ° C 〇 The sodium salt was prepared by treating 6.45 g (14.80 mmol) of the above acid compound in EtOH (100 mL) in 14.80 mL of IN NaOH. The organic solvent was removed in vacuo and the crude solid was dissolved in 1.2 liters of isopropanol under reflux. The final volume was reduced to 500 ml with a distillation solvent. Cool to room temperature to crystallize the sodium salt. The crystallized sodium salt was suspended in hydrazine 20, lyophilized in a dry ice bath and lyophilized to afford 6.00 g of the title compound. -35 - 1259080 Description of the invention (1) lH NMR (500 MHz, DMSO-d6) δ 7.63 (dd, 1H, 8.5 Hz, J2=2.6

Hz), 7.47 (dd, 1H, 9.7 Hz, J2 = 2.6 Hz), 7.33 (d, 2H, J=8.4 Hz)? 6.70 (d，2H，J=8.4 Hz), 6·06 (d, 1H, JAB=17.9 Hz), 5.76 (d，1H， JAB=17.9 Hz)，3.29 (m，1H)，3.08 (s，3H)，2.80 (m，1H)，2.69 (m， 1H)，2.55 (m，1H)，2.18 (m，2H)，1.93 (dd，1H，14.4 Hz，J2= 9.7 Hz)。Hz), 7.47 (dd, 1H, 9.7 Hz, J2 = 2.6 Hz), 7.33 (d, 2H, J=8.4 Hz)? 6.70 (d, 2H, J=8.4 Hz), 6·06 (d, 1H, JAB=17.9 Hz), 5.76 (d,1H, JAB=17.9 Hz), 3.29 (m,1H), 3.08 (s,3H), 2.80 (m,1H), 2.69 (m, 1H), 2.55 (m, 1H), 2.18 (m, 2H), 1.93 (dd, 1H, 14.4 Hz, J2 = 9.7 Hz).

實例1AExample 1A

( + /-)-[ 5-溴-4-(4-氯芊基）-7-氟-1，2,3,4-四氫環戊并[b]吲哚-3-基]乙酸（實例1，步驟4)之另一程序步驟1 ·· ( + /-)-(7-氟-1，2,3,4-四氫環戊并[b]4丨哚-3-基）乙酸二環己基胺（DCHA)鹽( + /-)-[ 5-Bromo-4-(4-chloroindolyl)-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid ( Example 1, Step 4) Another Procedure Step 1 ·· ( + /-)-(7-Fluoro-1,2,3,4-tetrahydrocyclopenta[b]4indol-3-yl)acetic acid Dicyclohexylamine (DCHA) salt

將含0.526 Μ 2-溴-4-氟苯胺之二甲苯溶液與（2-氧代環戊基）乙酸乙酷（1.5當量）及硫酸（0.02當量）一起加熱至回流20 小時。以Dean-Stark裝置將水共〉·弗移除。反應以NMR追2從， 20小時後，通常發現80-85%轉化成所需之亞胺中間物。反應混合物以1M碳酸氫鈉（0.2體積）洗滌15分鐘，且蒸發有機份。真空（0.5 mm Hg)蒸餾留下之漿料。在30°C下蒸餾留下之二甲苯，接著於50-110°C間回收過量之酮及未反應之苯胺；於11(M80°C下回收淡棕色透明液態亞胺餾份，純度為83%。接著將亞胺中間物添加於乙酸鉀（3當量）、四正丁基銨氯化物單水合物（1當量）、乙酸鈀（0.03當量）及N，N-二甲基乙醯胺之除氣混合物中（亞胺之最終濃度=0.365 M)。反應混合物加熱至11 5°C 5小時，且使其冷卻至室溫。接著添加3N KOH (3 當量），且使混合物室溫攪拌1小時。反應混合物以水（1 .〇體 -36- 1259080 l_ 丨發明說明續頁 \J^) - 積）稀釋，以甲苯（3 X 〇.75體積）洗務。水性相以3N HC[酸化至pH 1，且以第三丁基甲基鍵（2X 0.75體積）萃取。合併之有機份以水（0.75體積）洗條。於透明淡標色溶液中添加二環己基胺（1當量），且使溶液在室溫擾拌16小時。使鹽過遽’以乙酸乙酯、第三丁基甲基醚洗條’且使其乾燥’獲得褐色固態標題化合物。分析·· 94 A%。 lH NMR (500 mHz, CDC13) · δ 9.24 (s, 1Η), 7.16-7.08 (m, 2H), 6.82 (t, 1H), 6.2 (br, 2H), 3.6-3.5 (m, 1H), 3.04-2.97 (m, 2H), 2.88-2.70 (m，3H), 2.66 (dd，lH)，2.45-2.37 (m，1H)，2.13-2.05 (m，2.05)，1.83 (d，4H)，1.67 (d，2H)，1.55-1.43 (m，4H)，1.33-1.11 (m，6H)。步驟2: ( + /-)_(5-溴-7-氟-1，2,3,4-四氫環戊并[bp?丨哚-3-基）乙酸將含上述步驟1之DCHA鹽之二氯甲垸漿料（0.241 Μ溶液）冷卻至-20至-15°C。一次添加吡啶（2當量），且維持在-2〇至_15 °C下，於30至45分鐘内將溴（2.5當量）滴加於漿料中。（在溴添加約1 / 3時，反應混合物變稠，且需要攪拌流出物。最後，當溴添如約1/2時，混合物再度變“稀”）。添加完全後，再使反應混合物於_ 15 °C下老化一小時。接著於$分鐘内添加乙酸 (3.〇4當量），且逐份添加鋅粉（3.〇4當量）。（一部份鋅於-15°匸下添加，且使混合物老化約5分鐘，以確保持續放熱（約-1 5 。(：至-l〇t ))。約30分鐘内重複操作約5次之鋅。當不再發現放熱時，快速將其餘鋅加入。全部操作號時约3 0至4 5分鐘。添加完全後，使該批升溫至室溫，老化1小時且濃縮。反應混合物改成添加甲基第三丁基醚（MTBE，0.8當量）及10% -37- 1259080 發明說明續頁 (33) 乙酸水溶液（0.8體積）。混合物（鹽結晶’例如吡啶鑌）在室溫下老化1小時，且經s〇lka-fl〇c過濾。solka-floc螯以MTBE (約0.2 體積）洗滌且將濾液（雙相，MTBE/水性）移入萃取器中。有機相以水（0.8體積）洗滌。濃縮MTBE萃取液且加於異丙醇 (IPA，〇,25體積）中使化合物結晶。加水（0.25體積），且使該批老化1小時。於1小時内添加額外之水（0.33體積）。水添加完全後，再使該批老化1小時，且以30/70 IPA/水（0.1 5體積）洗滌。在+45°C下於烘箱中烘乾結晶之溴酸。步·驟3 : ( + /-)-[5-溴-4-(4-氯芊基）-7-氟-1，2,3,4-四氫環戊并[b] 啕哚-3-基]乙酸將步騾2之溴酸溶於二甲基乙醯胺（0.416 Μ溶液）中，且一次添加碳酸絶（2·5當量）。漿料中一次添加4-氣芊基氯（2.5當量），且將該批加熱至50°C 20小時。將該批冷卻至室溫，且於5分鐘内添加氫氧化鈉5>1(4.00當量）（溫度上升至+40^：)。反應在50°C下老化約3小時，冷卻至室溫，且移入l萃取器中。溶液以乙酸異丙酯（IPAc，2體積）稀釋，且冷卻至+ 15°c。溶液以5N HCI酸化至pH〜2。使層分離且以水（2 X 2體積）洗滌有機層。濃縮IPAc溶液，且移入IPA (0.8體積）中，使產物結晶。於2小時内加水（8升），且將該批過濾、，獲得標題化合物，分離產率88%。該批可在+40°C下乾燥24小時α * 實例2 (+ /- )- {4-[1-(4-氯本基）乙基]-氟-5-甲4元續酶基_ι，2,3,4 -四氫環戊并[b]4丨哚-3-基}乙酸 1259080 ^_ (34) 發明說明續頁The xylene solution containing 0.526 Μ 2-bromo-4-fluoroaniline was heated to reflux with 20-(2-oxocyclopentyl)acetic acid (1.5 eq.) and sulfuric acid (0.02 eq.). The water was removed using a Dean-Stark device. The reaction was followed by NMR. After 20 hours, it was generally found that 80-85% was converted to the desired imine intermediate. The reaction mixture was washed with 1 M sodium hydrogencarbonate (0.2 volume) for 15 min and evaporated. The slurry was distilled under vacuum (0.5 mm Hg). Distillation of xylene at 30 ° C, followed by recovery of excess ketone and unreacted aniline at 50-110 ° C; recovery of light brown transparent liquid imine fraction at 11 ° C (80 ° C, purity of 83 The imine intermediate is then added to potassium acetate (3 equivalents), tetra-n-butylammonium chloride monohydrate (1 equivalent), palladium acetate (0.03 equivalent) and N,N-dimethylacetamide. In the degassing mixture (final concentration of imine = 0.365 M). The reaction mixture was heated to 11 5 ° C for 5 hours and allowed to cool to room temperature. Then 3N KOH (3 eq.) was added and the mixture was stirred at room temperature 1 Hour. The reaction mixture was diluted with water (1. steroid - 36 - 1259080 l 丨丨说明 \ \ \ \ \ \ - - 。。。。。。。). The aqueous phase was extracted with 3N HCl [acidified to pH 1 and extracted with a <RTI ID=0.0>> The combined machine was washed with water (0.75 vol). Dicyclohexylamine (1 equivalent) was added to the clear pale color solution, and the solution was stirred at room temperature for 16 hours. The salt was dried <RTI ID=0.0></RTI> to <RTI ID=0.0> Analysis·· 94 A%. lH NMR (500 mHz, CDC13) · δ 9.24 (s, 1Η), 7.16-7.08 (m, 2H), 6.82 (t, 1H), 6.2 (br, 2H), 3.6-3.5 (m, 1H), 3.04 -2.97 (m, 2H), 2.88-2.70 (m,3H), 2.66 (dd,lH), 2.45-2.37 (m,1H),2.13-2.05 (m,2.05),1.83 (d,4H),1.67 (d, 2H), 1.55-1.43 (m, 4H), 1.33-1.11 (m, 6H). Step 2: (+ /-)_(5-bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta[bp?indol-3-yl)acetic acid will contain the DCHA salt of step 1 above. The methylene chloride slurry (0.241 Μ solution) is cooled to -20 to -15 °C. Pyridine (2 equivalents) was added in one portion and maintained at -2 to -15 ° C, and bromine (2.5 equivalents) was added dropwise to the slurry over 30 to 45 minutes. (When bromine is added about 1/3, the reaction mixture thickens and the effluent needs to be stirred. Finally, when the bromine is added, for example, about 1/2, the mixture becomes "thin" again). After the addition was completed, the reaction mixture was aged at -15 ° C for one hour. Then, acetic acid (3. 4 equivalents) was added over $ minutes, and zinc powder (3. 4 equivalents) was added portionwise. (A portion of the zinc is added at -15 ° 匸 and the mixture is allowed to age for about 5 minutes to ensure a sustained exotherm (about -1 5 (. to -l〇t)). Repeat for about 5 times in about 30 minutes. Zinc. When the exotherm is no longer found, the remaining zinc is quickly added. The total operation number is about 30 to 45 minutes. After the addition is complete, the batch is allowed to warm to room temperature, aged for 1 hour and concentrated. Addition of methyl tert-butyl ether (MTBE, 0.8 eq.) and 10% -37 to 1259080 Description of the invention (33) Aqueous acetic acid (0.8 vol). Mixture (salt crystals such as pyridinium) aged at room temperature 1 Hour, and filtered through s〇lka-fl〇c. The soka-floc chelate was washed with MTBE (about 0.2 vol) and the filtrate (biphasic, MTBE/aqueous) was transferred to the extractor. The organic phase was washed with water (0.8 vol) The MTBE extract was concentrated and added to isopropanol (IPA, hydrazine, 25 vol) to crystallize the compound. Water (0.25 vol) was added and the batch was aged for 1 hour. Additional water (0.33 vol) was added over 1 hr. After the water is added completely, the batch is aged for 1 hour and at 30/70 IPA/water (0.1 5 vol) Washing. The crystallized bromic acid is dried in an oven at +45 ° C. Step 3 : ( + /-)-[5-bromo-4-(4-chloroindolyl)-7-fluoro-1, 2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid The bromic acid of step 2 is dissolved in dimethylacetamide (0.416 hydrazine solution), and carbonic acid is added at once ( 2. 5 eq.) 4-sulfonyl chloride (2.5 eq.) was added in one portion of the slurry, and the batch was heated to 50 ° C for 20 hours. The batch was cooled to room temperature and hydroxide was added over 5 minutes. Sodium 5 > 1 (4.00 eq.) (temperature rises to +40^:) The reaction is aged at 50 ° C for about 3 hours, cooled to room temperature, and transferred to an extractor. The solution is isopropyl acetate (IPAc, 2 volumes) diluted and cooled to + 15 ° C. The solution was acidified to pH ~ 2 with 5 N HCI. The layers were separated and the organic layer was washed with water (2 X 2 volume). The IPAc solution was concentrated and transferred to IPA (0.8 vol) The product was crystallized. Water (8 L) was added over 2 hours, and the mixture was filtered to give the title compound, isolated yield 88%. The batch was dried at +40 ° C for 24 hours α * Example 2 ( + /- )- {4-[1-(4-Chlorobenzyl)ethyl]-fluoro-5-methyl 4-hydroxylase _ , 2,3,4 - tetrahydro-cyclopenta [b] 4-3-yl} acetic acid Shu ^ _ 1259080 (34) Continued invention is described on page

含1.3克貫例1、步驟3之酸甲基酯（其係在四氫呋喃中以重氮甲燒使相對應之酸酯化製備）之50毫升乙腈溶液中添加 2.03克1-(1-漠乙基）_4_氯苯及6 〇1克碳酸铯。所得混合物加熱至回流且劇烈攪掉3小時。接著，使反應混合物冷卻至室溫’以50毫升乙酸乙酯稀釋，經過濾且使溶劑蒸發。殘留物以快速層析（矽膠，4% EtOAc/己烷）純化，獲得1.41克所需之N-爷基化產物’依據iH nmR分析約為非立體異構物之1 : 1混合物。Add 2.0 g of 1-(1-Mobil B) to a solution of 1.3 g of the acid methyl ester of Example 1, Step 3, which is prepared by diazotethane in tetrahydrofuran to prepare the corresponding acid esterification. Base) _4_ chlorobenzene and 6 〇 1 gram of cesium carbonate. The resulting mixture was heated to reflux and vigorously stirred for 3 hours. Then, the reaction mixture was cooled to room temperature and diluted with 50 ml of ethyl acetate. The residue was purified by flash chromatography (EtOAc EtOAc EtOAc) elute

將溶解上述酯（1.2克）之80毫升NMP中添加2.63克甲烷磺酸鈉鹽及3.7克Cu(I)Br。所得懸浮液在N2流中除氣，加熱至140 t且劇烈攪拌8小時。接著使反應混合物冷卻至室溫，且以 500毫升乙酸乙酯及500毫升己烷稀釋。所得混合物經矽膠墊過濾，以EtOAc進一步溶離。濾液濃縮至體積約3〇0毫升，且以水及食鹽水洗滌。使有機相分離且以無水Na2S04脫水，經過濾且濃縮。粗物質在矽膠上以30% EtOAc/己烷溶離之快速層析純化，獲得1·〇克磺化物質。使用10毫升在含10毫升THF 及10毫升-MeOH溶劑混合物中之2Ν NaOH，在室溫下水解3小時，成為相對應之酸。反應混合物以1M HC1水溶液中和且以EtOAc萃取。分離之有機相以無水硫酸鈉脫水，經過濾且蒸發，獲得粗的酸。使用製備用HPLC (Zobax，含0.2% AcOH -39- 1259080 (35) 發明說明續頁之30% EtOAC/己烷）分離二非立體異構物，獲得300毫克非立體異構物A (駐留時間較短）及210毫克非立體異構物b (駐留時間較長）。非立體異構物 B : NMR (丙酮-d6) δ 10.70 (br s，1H)，7.66 (dd， 1H)，7·56 (dd，1H)，7.32 (d，2H)，6·95 (d, 2H)，6·91 (q，1H)，3·39 (s, 3H)，3.05-3.00 (m，1H)，2.90- 2,75 (m，2H)，2·70 (dd，1H)，2.44 (dd, 1H), 2.43-2.34 (m, 1H)，2.21 (dd，1H)，2.11 (d，3H)。MS (-APCI) m/z 448·0(Μ-ΗΓ。To 80 ml of NMP in which the above ester (1.2 g) was dissolved, 2.63 g of sodium methanesulfonate and 3.7 g of Cu(I)Br were added. The resulting suspension was degassed in a stream of N2, heated to 140 t and stirred vigorously for 8 hours. The reaction mixture was then cooled to room temperature and diluted with EtOAc (EtOAc) The resulting mixture was filtered through a pad of Celite and further eluted with EtOAc. The filtrate was concentrated to a volume of about 3 mL and washed with water and brine. The organic phase was separated and dried over anhydrous Na2SO4 filtered and concentrated. The crude material was purified by flash chromatography eluting with 30% EtOAc/hexanes eluting Using 10 ml of 2 NaOH in a mixture of 10 ml of THF and 10 ml of -MeOH solvent, the mixture was hydrolyzed at room temperature for 3 hours to become the corresponding acid. The reaction mixture was neutralized with 1M aqueous HCI andEtOAc. The separated organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give crude. Separation of the di-non-stereoisomers using preparative HPLC (Zobax, containing 0.2% AcOH-39-1259080 (35), 30% EtOAC/hexane), to obtain 300 mg of non-stereoisomer A (residence time) Shorter) and 210 mg of non-stereoisomer b (longer residence time). Non-stereoisomer B: NMR (acetone-d6) δ 10.70 (br s, 1H), 7.66 (dd, 1H), 7.56 (dd, 1H), 7.32 (d, 2H), 6·95 (d , 2H),6·91 (q,1H),3·39 (s, 3H), 3.05-3.00 (m,1H), 2.90-2,75 (m,2H),2·70 (dd,1H) , 2.44 (dd, 1H), 2.43-2.34 (m, 1H), 2.21 (dd, 1H), 2.11 (d, 3H). MS (-APCI) m/z 448·0 (Μ-ΗΓ.

實例2AExample 2A

( + /-)-{4·[ 1·(4·氯苯基）乙基]-7-氟-5-甲烷續醯基-1，2,3,4-四氫環戊并[b] 41嗓-3-基}乙酸之另一合成方法含6 · 5 2克實例1、步驟3之酸甲基醋（其係在四氫咬喃中以( + /-)-{4·[ 1·(4·chlorophenyl)ethyl]-7-fluoro-5-methane hydrazino-1,2,3,4-tetrahydrocyclopenta[b] Another synthetic method of 41嗓-3-yl}acetic acid contains 6 · 5 2 g of the acid methyl vinegar of Example 1, Step 3 (which is in tetrahydroanthracene)

重氮甲烷使相對應之酸醋化製備）之160毫升NMP_液中依序添加10.2克甲烷磺酸納鹽及19克CuI。所得懸浮液在N2流中加熱至15 0 °C，且劇烈彳覺拌*小時。接著使反應/昆合物冷卻至室溫，且以500毫升己酸乙醋及500毫升己燒稀釋。所得混合物經矽膠墊過濾，以Et〇AC進一步溶離。遽液滚縮至體積約300毫升，且以水及食鹽水洗務。使有機相分離且以無水 Na2S04脫水，經過濾且濃縮。粗物質在碎膠上以3〇% Et〇Ac/ 己烷溶離之快速屠析純化’獲得4·7克績化物質’將其溶於 200毫升二氣甲烷中。於所得溶液中添加3.39克心氣苯基甲醇及5.68克三苯基膦，接著逐份添加4·99克二·第三丁基偶氮二叛酸醋。反應混合A 物置於矽膠管柱中’ 在室溫下攪摔3小時接著濃縮。將殘留且以5% EtOAc/己烷溶離，獲得5.1克標 -40- 1259080 _ (^\ I發明說明續頁題化合物之甲酯，依據W NMR分析約為非立體異構物之1 : 1混合物。重複實例2所述之水解及純化步驟，獲得標題之酸。實例3 (+ /-)_[9-(4-氯苄基）-6-氟-8-甲烷磺醯基-2,3,4,9-四氫-1沁咔唑 -1-基]乙酸To the 160 ml of NMP_ liquid prepared by the corresponding acidification of diazomethane, 10.2 g of sodium methanesulfonate and 19 g of CuI were added in this order. The resulting suspension was heated to 150 °C in a stream of N2 and stirred vigorously for an hour. The reaction/compound was then cooled to room temperature and diluted with 500 ml of ethyl hexanoate and 500 ml of hexane. The resulting mixture was filtered through a pad of silica gel and further eluted with Et. The sputum was rolled to a volume of about 300 ml and washed with water and saline. The organic phase was separated and dried over anhydrous Na2SO4 filtered and concentrated. The crude material was purified by rapid pyrolysis on 3 g of Et EtOAc / hexanes to give a 4·7 gram of material, which was dissolved in 200 ml of di-methane. To the resulting solution, 3.39 g of heart phenylmethanol and 5.68 g of triphenylphosphine were added, followed by the addition of 4.99 g of di-tert-butyl azobis bismuth vinegar. The reaction mixture A was placed in a silica gel column' and stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in 5% EtOAc / hexanes to give the title compound of the title compound of the title compound. Mixture. The hydrolysis and purification steps described in Example 2 were repeated to obtain the title acid. Example 3 (+ /-)_[9-(4-chlorobenzyl)-6-fluoro-8-methanesulfonyl-2, 3,4,9-tetrahydro-1oxazol-1-yl]acetic acid

步驟1.( + /-)-(8-’/臭-6-氣-2,3,4,9-四鼠-11'1-17卡唆-1-基）乙故乙@§Step 1. ( + /-)-(8-'/odor-6-gas-2,3,4,9-four mouse-11'1-17 cardin-1-yl)

於含7.24克（2-溴-4-氟苯基）聯氨鹽酸鹽之100毫升乙酸懸浮液中添加5.5克2-(2-氧代環己基）乙酸乙酯。使所得混合物加熱至回流1小時。接著，添加10毫升乙醇，且使反應混合物回流加熱隔夜。蒸發溶劑且殘留物以EtOAc稀釋。依序以飽和NaHC〇3水溶液、水及食鹽水洗滌。分離有機層且以無水硫酸鈉脫水，經過濾且蒸發。殘留在矽膠（5% EtOAc/己烷）上快速¥析純化，獲得3.12克所需化合物。咕 NMR (丙酮-d6) δ 9.97 (br s，1H)，7.34 (dd, 1H)，7·13 (dd，1H)， 7.09 (dd，1H)，4.16 (q，2H)，3.43·3.35 (m，5H)，3.05-2.88 (m，1H)， 2.76-2.53 (m, 3H)? 2.10-2.00 (m, 1H), 1.96-1.87 (m, 1H), 1.82-1.72 -41 - 1259080 發明說明續頁 (37) (m, H)，1.72-1.64 (m, 1H)，1.23 (t，3H)。步驟2 : ( + /-)-[8-溴-9-(4-氯芊基）-6-氟-2,3,4,9-四氫-1沁咔唑-1-基]乙酸乙酯To a suspension of 7.24 g (2-bromo-4-fluorophenyl) hydrazine hydrochloride in 100 ml of acetic acid, 5.5 g of ethyl 2-(2-oxocyclohexyl)acetate was added. The resulting mixture was heated to reflux for 1 hour. Next, 10 ml of ethanol was added, and the reaction mixture was refluxed and heated overnight. The solvent was evaporated and the residue was diluted with EtOAc. The solution was washed with a saturated aqueous solution of NaHC 3 , water and brine. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc)咕 NMR (acetone-d6) δ 9.97 (br s, 1H), 7.34 (dd, 1H), 7·13 (dd, 1H), 7.09 (dd, 1H), 4.16 (q, 2H), 3.43·3.35 ( m,5H), 3.05-2.88 (m,1H), 2.76-2.53 (m, 3H)? 2.10-2.00 (m, 1H), 1.96-1.87 (m, 1H), 1.82-1.72 -41 - 1259080 Continued on page (37) (m, H), 1.72-1.64 (m, 1H), 1.23 (t, 3H). Step 2: ( + /-)-[8-Bromo-9-(4-chloroindolyl)-6-fluoro-2,3,4,9-tetrahydro-1oxazol-1-yl]acetate B ester

含3· 12克步驟1中製備之酯及3.62克Μ臭甲基-4-氯苯之30毫升乙腈溶液中添加5.74克碳酸铯。所得混合物在回流下劇烈攪拌3小時。接著使其冷卻至室溫，以最小量EtOAc稀釋，經過濾且蒸發。殘留物在矽膠（50%甲苯/己烷）上快速層析純化，獲得4.1克標題化合物。巾 NMR (丙酮-d6) δ 7.32 (d，2H), 7.24 (dd，1H)，7.13 (dd，1H), 6.86 (d，2H), 6.00及 5.65 (AB q，2H)，4.15-4.05 (m，2H)，3.44-3.35 (m, 1H), 2.88-2.76 (m, 1H), 2.65-2.52 (m, 3H), 2.00-1.80 (m, 4H)? 1.22 (t，3H) 〇步驟3 . ( + /- )- [9-(4-氣卞基）-6 -氣-8-甲坑確驢基-2,3,4,9-四鼠 -1H-咔唑-1-基]乙酸於含478毫克步驟2中製備之酯之8毫升NMP溶液中依序添加5 10毫克甲烷磺酸鈉鹽及950毫克Cul (I)。所得混合物在N2 流中除氣，接著在劇烈攪拌下於140°C下加熱8小時。使反應混合物冷卻至室溫，以最小量EtOAc/己烷之1 : 1混合物稀釋。所得混合物經矽膠墊過濾，以EtOAc進一步溶離。濾液濃縮至體積約5 0毫升，且以水及食鹽水洗條。收集有機相 1259080 發明說明續頁且以無水硫酸鈉脫水，經過濾且蒸發。粗物質在矽膠（30% EtOAc/己烷）上快速層析純化，獲得320毫克磺化物質，使其溶於5毫升THF加上5毫升甲醇中。所得溶液中添加5毫升之 2N NaOH，且使所得混合物在室溫攪摔6小時。反應混合物以1M HC1水溶液中和，且以EtOAc萃取。分離之有機相以無水硫酸鈉脫水，經過濾且蒸發。殘留物在劇烈攪拌下與己烷回流0.5小時。在劇烈攪拌下使所得混合物冷卻至室溫，且過濾獲得278克所需之酸。巾 NMR (500 MHz，丙酮-d6) δ 10.73 (br s，IH)，7.57 (d，1H)，7.56 (d, 1H), 7.29 (d, lH)，6.67(d,2H，），6.47&5.61(ABq，2H)， 3·27-3.21(πι，1H)，2.98 (s，3H)，2.85 (dd，1H)，2.76-2.55 (m，3H)， 2.00-1.84 (m，3H), 1.82-1.73 (m，1H)。MS (-APCI) m/z 448.0 (M-H) 〇實例4 [4-(4-氯芊基）-7-氟-5-甲烷磺醯基-1-氧代-1,2,3,4-四氫環戊并 >]啕哚-3-基]乙酸〇5.74 g of cesium carbonate was added to a solution of 3.12 g of the ester prepared in the step 1 and 3.62 g of the deodorized methyl-4-chlorobenzene in 30 ml of acetonitrile. The resulting mixture was vigorously stirred under reflux for 3 hours. It was then cooled to room temperature, diluted with a minimum EtOAc, filtered and evaporated. The residue was purified by flash chromatography eluting EtOAc EtOAc Towel NMR (acetone-d6) δ 7.32 (d, 2H), 7.24 (dd, 1H), 7.13 (dd, 1H), 6.86 (d, 2H), 6.00 and 5.65 (AB q, 2H), 4.15-4.05 ( m,2H),3.44-3.35 (m, 1H), 2.88-2.76 (m, 1H), 2.65-2.52 (m, 3H), 2.00-1.80 (m, 4H)? 1.22 (t,3H) 〇Step 3 ( + /- )- [9-(4-Galylidene)-6 -Gas-8-Jetengqiji-2,3,4,9-tetra-rat-1H-carbazol-1-yl] Acetic acid 510 mg of sodium methanesulfonate and 950 mg of Cul (I) were added sequentially to 8 ml of NMP solution containing 478 mg of the ester prepared in Step 2. The resulting mixture was degassed in a stream of N2 and then heated at 140 ° C for 8 hours with vigorous stirring. The reaction mixture was allowed to cool to room temperature and diluted with a minimum of 1:1 mixture of EtOAc/hexanes. The resulting mixture was filtered through a pad of EtOAc (EtOAc). The filtrate was concentrated to a volume of about 50 ml and washed with water and brine. Collect organic phase 1259080 Description of the invention Continued and dehydrated with anhydrous sodium sulfate, filtered and evaporated. The crude material was purified by flash chromatography eluting eluting eluting eluting eluting 5 ml of 2N NaOH was added to the resulting solution, and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was neutralized with aq. The separated organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was refluxed with hexane for 0.5 hour with vigorous stirring. The resulting mixture was cooled to room temperature with vigorous stirring, and filtered to give 278 g of desired acid. NMR (500 MHz, acetone-d6) δ 10.73 (br s, IH), 7.57 (d, 1H), 7.56 (d, 1H), 7.29 (d, lH), 6.67 (d, 2H,), 6.47 &;5.61(ABq,2H), 3·27-3.21(πι,1H), 2.98 (s,3H), 2.85 (dd,1H), 2.76-2.55 (m,3H), 2.00-1.84 (m,3H) , 1.82-1.73 (m, 1H). MS (-APCI) m/z 448.0 (MH) 〇 Example 4 [4-(4-Chloromethyl)-7-fluoro-5-methanesulfonyl-1-oxo-1,2,3,4- Tetrahydrocyclopentazone>]indol-3-yl]acetate

步驟1· [5-〉臭-4-(4-氣卞基）-7 -氣-1-氧代-1，2,3,4 -四鼠J哀戍并[b] 吲哚-3-基]乙酸甲酯Step 1· [5->Smelly 4-(4-amidino)-7-Gas-1-oxo-1,2,3,4 -4 Mice J mourning and [b] 吲哚-3- Methyl acetate

-43 - 1259080 __ 發明說明續頁 (39) --_ 以2.52克DDQ處理含實例1步.驟5化合物之甲酿（1.00克’以過量之重氮甲烷處理相對應之酸製備）之丨〇毫升9 : i THF/H2O溶液。使反應混合物於室溫授拌隔夜。此時將反應混合物倒入含EtOAc及食鹽水之分液漏斗中。合併之有機層以水、食鹽水洗蘇，以無水MgS〇4脫水且濃縮。所仔為貝以 30% EtOAc/己坑溶離之快速層析進一步純化。重複層析私序二次。獲得350毫克灰色固態上述之酮。步驟2 : [4-(4-氣苄基）-7-氟〇-甲烷磺醯基-1-氧代-1，2,3,4-四氫環戊并[b]啕哚-3-基]乙酸含於4毫升NMP之步驟1溴化物（200毫克）以320毫克Cul及 175毫克CH3S02Na處理。使氮氣泡經過反應混合物約一分鐘，接著在13〇°C下加熱混合物六小時。此時’將反應混合物冷卻至室溫，以EtOAc稀釋且經矽膠墊過濾’殘留物以額外之EtOAc洗滌。有機層以水、食鹽水洗滌’以無水MgS〇4 脫水及濃縮。所得之油以50% EtOAc/己烷溶離之快速層析純化，獲得54毫克灰白色固態相對應之甲基諷。在5毫升THF/H20 (1 ·· 1)及5毫升MeOH之上述甲酯以1毫升 IN HC1溶液處理。使混合物在室溫攪拌2小時。此時’以1N HC1使反應混合物酸化，且倒入含水及Et0Ac之分液漏斗中。使層分離且以EtOAc萃取水層。合併之有機層以水、食鹽水洗滌，以無水Na2S〇4脫水且濃縮。所得物質以含1% AcOH之100% EtOAc溶離之快速層析進一步純化，獲得灰白色固態標題之酸26毫克。 4 NMR (500 MHz，丙酮〇 δ 11.0 (br，1H), 7.85 (m，1H)，7·80 -44 - 1259080 發明說明續頁 (40) (m，1H)，7.38 (d，J=8 Hz，2H)，7·04 (d，J=8 Hz，2H)，6.42 (d，Jab=18 Hz，1H)，6.08 (d，Jab=18 Hz，1H)，3.78 (m，1H)，3.28 (m，1H)，3.10 (m，1H)，3.05 (s，3H)，2.65 (m，2H)。 MS (-APCI) m/z 448.2 (M-H)、 -45 --43 - 1259080 __ Description of the invention (1) --_ Treatment with 2.52 DDQ of the formula 1 and the preparation of the compound of step 5 (1.00 g 'prepared with the corresponding acid in excess of diazomethane) 〇ml 9 : i THF/H2O solution. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into a sep. funnel containing EtOAc and brine. The combined organic layers were washed with water and brine, dried over anhydrous MgS 4 and concentrated. The residue was further purified by flash chromatography using 30% EtOAc/hexanes. Repeat the chromatographic private sequence twice. Obtain 350 mg of the above-mentioned ketone in a gray solid state. Step 2: [4-(4-Galybenzyl)-7-fluoroindole-methanesulfonyl-1-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-3- The acetic acid contained in step 1 of 5 ml of NMP (200 mg) was treated with 320 mg of Cul and 175 mg of CH3S02Na. Nitrogen gas bubbles were passed through the reaction mixture for about one minute, followed by heating the mixture at 13 ° C for six hours. At this time the reaction mixture was cooled to EtOAc EtOAc EtOAc. The organic layer was washed with water and brine and dried over anhydrous Mgs. The oil thus obtained was purified by flash chromatography eluting with 50% EtOAc / hexane to afford the crude product of 54 mg as a white solid. The above methyl ester in 5 ml of THF/H20 (1··1) and 5 ml of MeOH was treated with 1 ml of IN HCl solution. The mixture was stirred at room temperature for 2 hours. At this time, the reaction mixture was acidified with 1N HCl and poured into a sep. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na? The material was further purified by flash chromatography eluting with EtOAc (EtOAc) 4 NMR (500 MHz, acetone 〇 δ 11.0 (br, 1H), 7.85 (m, 1H), 7·80 -44 - 1259080 Description of the invention (40) (m, 1H), 7.38 (d, J=8 Hz, 2H), 7·04 (d, J=8 Hz, 2H), 6.42 (d, Jab=18 Hz, 1H), 6.08 (d, Jab=18 Hz, 1H), 3.78 (m, 1H), 3.28 (m,1H), 3.10 (m,1H), 3.05 (s,3H), 2.65 (m,2H) MS (-APCI) m/z 448.2 (MH), -45 -

Claims

Work 2599 Secret 1〇1476 Patent Application Chinese Application Patent Renewal (April 95) j Japanese repair (more} original copy, application patent scope 1. A compound of formula I, which has the three-dimensional structure shown below : (〇)n

Wherein η is 0 or 1; m is 1; the heart is Η, (^-ί: 3 alkyl, halogenated Ci-q alkyl or cyclopropyl; R2 is 4-chlorophenyl or 2,4,6- Trichlorophenyl. 2. The compound of claim 1 wherein n is 0. 3. The compound of claim 1 wherein n is 1. 4. If the scope of claim 1 is a compound, wherein m is 1. 5. A compound of the first aspect of the patent application, wherein the heart is Η. 6. If the compound of claim 1 is a compound, 1 of which is CH3. The compound of the above formula 1, wherein R2 is 4-chlorophenyl. 8. The compound of claim 1, wherein R2 is 2,4,6-trichlorophenyl. Compound [4-(4-chloroindolyl)-7-fluoro-5-(methanesulfonyl)-1,2,3,4-tetrahydrocyclopenta[b], indol-3-yl]acetic acid , {4·[1-(4-chlorophenyl)ethyl]-7-gas-5-indole acid group-1,2,3,4-tetrazine 5 pentylene [b]4丨嗓-3-yl}acetic acid, and [4_(4_chloroindolyl)-7-murine-5-a pituitary-1-oxo-1,2,3,4-tetrachloro- [bp?丨哚-3-yl]acetic acid, or patent application Continuation page 1259080 Its pharmaceutically acceptable salt. 10. Compound (-)-[4-(4·chloroindolyl)-7-fluoro-5-(methanesulfonyl)-1,2,3,4 - tetrahydrocyclopenta[b](9)indol-3-yl]acetic acid and its pharmaceutically acceptable salt. 11. A compound ( + /-)-{ 4-[4-[ 1-(4-chlorophenyl) Ethyl]-7-fluoro-5-methanesulfonyl-1,2,3,4·tetrahydrocyclopenta[b]indol-3-yl}acetic acid and its pharmaceutically acceptable salt. The compound [4-(4-chlorobenzyl)-7.fluoro-5-decanesulfonyl-1-oxo-1,2,3,4-tetrahydro-cyclopenta[b]M|哚- 3-based]acetic acid and a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition for preventing or reversing undesired symptoms caused by prostaglandin D2, which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable compound thereof A pharmaceutical composition for treating or preventing a prostaglandin D2 modulating disease, comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier thereof. 1 to 4 of the pharmaceutical composition, further comprising a cholesterol lowering agent. 16. A pharmaceutical combination as claimed in claim 15 And wherein the cholesterol lowering agent is Acid. If the pharmaceutical composition of claim 16 of the patent application further comprises Η MG - C ο A pro-enzyme inhibitor. 18. The pharmaceutical composition according to any one of the preceding claims, wherein the prostaglandin D 2 modulating disease is arteriosclerosis.